WO2021256902A1 - 신규한 링커로 결합된 2종 이상의 아릴 또는 헤테로아릴을 포함하는 카르보노하이드라조노일 디시아나이드 화합물 및 이의 용도 - Google Patents
신규한 링커로 결합된 2종 이상의 아릴 또는 헤테로아릴을 포함하는 카르보노하이드라조노일 디시아나이드 화합물 및 이의 용도 Download PDFInfo
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- WO2021256902A1 WO2021256902A1 PCT/KR2021/007694 KR2021007694W WO2021256902A1 WO 2021256902 A1 WO2021256902 A1 WO 2021256902A1 KR 2021007694 W KR2021007694 W KR 2021007694W WO 2021256902 A1 WO2021256902 A1 WO 2021256902A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- carbonohydrazonoyl dicyanide
- phenyl
- pyridin
- carbonohydrazonoyl
- dicyanide
- Prior art date
Links
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- ZFCHNZDUMIOWFV-UHFFFAOYSA-N pyrimidine-2-carboxylic acid Chemical compound OC(=O)C1=NC=CC=N1 ZFCHNZDUMIOWFV-UHFFFAOYSA-N 0.000 description 1
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- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- KSAVQLQVUXSOCR-UHFFFAOYSA-M sodium lauroyl sarcosinate Chemical compound [Na+].CCCCCCCCCCCC(=O)N(C)CC([O-])=O KSAVQLQVUXSOCR-UHFFFAOYSA-M 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
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- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
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- ZPHGMBGIFODUMF-UHFFFAOYSA-N thiophen-2-ylmethanol Chemical compound OCC1=CC=CS1 ZPHGMBGIFODUMF-UHFFFAOYSA-N 0.000 description 1
- QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 description 1
- VNNLHYZDXIBHKZ-UHFFFAOYSA-N thiophene-2-sulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CS1 VNNLHYZDXIBHKZ-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
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- 229930003799 tocopherol Natural products 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- WKOLLVMJNQIZCI-UHFFFAOYSA-N vanillic acid Chemical compound COC1=CC(C(O)=O)=CC=C1O WKOLLVMJNQIZCI-UHFFFAOYSA-N 0.000 description 1
- TUUBOHWZSQXCSW-UHFFFAOYSA-N vanillic acid Natural products COC1=CC(O)=CC(C(O)=O)=C1 TUUBOHWZSQXCSW-UHFFFAOYSA-N 0.000 description 1
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- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/76—Nitrogen atoms to which a second hetero atom is attached
- C07D213/77—Hydrazine radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/08—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D237/14—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D333/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Definitions
- the present invention relates to a novel carbonohydrazonoyl dicyanide compound comprising two or more types of aryl or heteroaryl joined by a linker and uses thereof.
- Tau protein (tau( ⁇ ) protein) is a microtubule-associated protein (MAP) mainly expressed in the axons of neurons with a molecular weight of 50,000 to 70,000, and serves to stabilize microtubules, and by phosphorylation represents molecular diversity.
- tau has 6 isoforms by insertion of 29 or 58 amino acid residues in the N-terminal region, and alternative splicing of the C-terminal 3 or 4 repeats (referred to as microtubule binding sites) by mRNA splicing. This is created
- tau stabilizes microtubules by promoting growth from axons and neuronal cell polarization.
- tau is dissociated from microtubules, leading to insoluble aggregation.
- NFTs neurofibrillary tangles
- Binding affinity for tau microtubules is also actively regulated by phosphorylation of tau, which results in a dynamic rearrangement of the microtubule network.
- tau When tau is abnormally and excessively phosphorylated, it disturbs the balance of this dynamic rearrangement and sharply reduces the affinity for microtubules.
- tau protein aggregates are mainly found in the cell body and dendrites of nerve cells, and are called neurofibrillary tangles (NFT) and neuropil threads. Looking at the microstructure of the neurofibrillar, it is composed of paired helical filaments (PHFs) in which tau protein is tangled like a fine thread, and unlike normal tau protein, it is aggregated and hyperphosphorylated. Abnormal tau protein aggregation also occurs in tauopathy. It is not known exactly what role this tau protein aggregation plays in the deepening stage of tauopathy, but it appears similar to the aggregation phenomenon commonly seen in general degenerative brain diseases.
- PHFs paired helical filaments
- tau protein-mediated diseases specifically transmit signals through certain mechanisms and are toxic It has not been identified yet, and there is no clear treatment or treatment available to treat these diseases.
- One object of the present invention is to provide a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
- L is -NHCO-, -CONH-, -NHSO 2 -, -SO 2 NH-, or -(straight or branched C 0-3 alkylene)'-O-(straight or branched C 0-3 alkylene )"-;
- R 1 is hydrogen, C 1-6 alkyl, or C 1-6 alkylcarbonyl
- (Het)Ar 1 is C 6-10 arylene or 5-10 membered heteroarylene
- (Het)Ar 2 is C 6-10 aryl or 5-10 membered heteroaryl
- the C 6-10 aryl (ene) and 5-10 membered heteroaryl (ene) are each independently unsubstituted or C 1-6 alkyl, C 1-6 alkoxy, halogen, cyano, C 1-6 haloalkyl and Substituted with one or more selected from the group consisting of C 1-6 haloalkoxy.
- Another object of the present invention is to provide a method for preparing the compound.
- Another object of the present invention is to provide a composition for inhibiting tau protein aggregation comprising the compound as an active ingredient.
- Another object of the present invention is to provide a composition for inhibiting tau protein hyperphosphorylation comprising the compound as an active ingredient.
- Another object of the present invention is to provide a pharmaceutical composition for preventing or treating diseases caused by aggregation or hyperphosphorylation of tau protein comprising the compound as an active ingredient.
- Another object of the present invention is to provide a method for preventing or treating a disease caused by aggregation or hyperphosphorylation of tau protein, comprising administering the pharmaceutical composition to an individual in need thereof.
- the carbonohydrazonoyl dicyanide compound comprising two or more aryls or heteroaryls bonded by a novel linker of the present invention can effectively inhibit aggregation and/or hyperphosphorylation of tau protein, a disease caused by this For example, it can be usefully used for preventing or treating Alzheimer's disease and various tauopathy.
- a first aspect of the present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
- L is -NHCO-, -CONH-, -NHSO 2 -, -SO 2 NH-, or -(straight or branched C 0-3 alkylene)'-O-(straight or branched C 0-3 alkylene )"-;
- R 1 is hydrogen, C 1-6 alkyl, or C 1-6 alkylcarbonyl
- (Het)Ar 1 is C 6-10 arylene or 5-10 membered heteroarylene
- (Het)Ar 2 is C 6-10 aryl or 5-10 membered heteroaryl
- the C 6-10 aryl (ene) and 5-10 membered heteroaryl (ene) are each independently unsubstituted or C 1-6 alkyl, C 1-6 alkoxy, halogen, cyano, C 1-6 haloalkyl and Substituted with one or more selected from the group consisting of C 1-6 haloalkoxy.
- L is -NHCO-, -CONH-, -NHSO 2 -, -SO 2 NH-, -O-, -O-CH 2 -, -O-(CH 2 ) 2 -, or -O-CH(CH 3 )-, but is not limited thereto.
- R 1 is hydrogen, methyl, or acetyl
- (Het)Ar 1 is phenylene, pyridinylene, pyrazinylene, pyrimidinylene, pyrazolylene, pyridazinylene, thiophenylene, benzothiazolylene, thiazolopyridinylene, quinoxalinylene, thia zolylene, isoxazolylene, oxazolylene, furanylene, benzimidazolylene, benzothiophenylene, or benzoxazolylene;
- (Het)Ar 2 is phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyridazinyl, thiophenyl, benzothiazolyl, thiazolopyridinyl, quinoxalinyl, thiazolyl, isoxazolyl, oxazolyl , furanyl, benzoimidazolyl, benzothiophenyl, or benzoxazolyl;
- the (Het)Ar 1 and (Het)Ar 2 may each independently be unsubstituted or substituted with one or more selected from the group consisting of methyl, methoxy, fluoro, chloro, cyano, and trifluoromethyl. , but not limited thereto.
- R 1 is hydrogen, methyl, or acetyl
- (Het)Ar 1 is phenylene, pyridinylene, or thiazolopyridinylene
- (Het)Ar 2 is phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyridazinyl, thiophenyl, benzothiazolyl, quinoxalinyl, thiazolyl, isoxazolyl, oxazolyl, furanyl, benzo imidazolyl, benzothiophenyl, or benzoxazolyl;
- the (Het)Ar 1 and (Het)Ar 2 may each independently be unsubstituted or substituted with one or more selected from the group consisting of methyl, methoxy, fluoro, chloro, cyano, and trifluoromethyl. , but not limited thereto.
- the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- Acetyl(3-methyl-4-(4-methylbenzyloxy)phenyl)carbonohydrazonoyl dicyanide may be acetyl(3-methyl-4-(4-methylbenzyloxy)phenyl)carbonohydrazonoyl dicyanide.
- these compounds may be compounds represented by the formula of Table 1 below.
- the compound of the present invention may exist in the form of a pharmaceutically acceptable salt.
- a pharmaceutically acceptable salt an acid value formed by a pharmaceutically acceptable free acid is useful.
- pharmaceutically acceptable salt refers to any of the compounds at a concentration having an effective action that is relatively non-toxic and harmless to a patient, and the side effects due to the salt do not reduce the beneficial efficacy of the compound represented by the formula (1). means any organic or inorganic addition salt of
- Acid addition salts are prepared by conventional methods, for example, by dissolving the compound in an aqueous solution of an excess of acid and precipitating the salt with a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equal molar amounts of compound and acid or alcohol (eg glycol monomethyl ether) in water may be heated, and then the mixture may be evaporated to dryness, or the precipitated salt may be filtered off with suction.
- a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile.
- Equal molar amounts of compound and acid or alcohol (eg glycol monomethyl ether) in water may be heated, and then the mixture may be evaporated to dryness, or the precipitated salt may be filtered off with suction.
- organic acids and inorganic acids can be used as free acids, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. can be used as inorganic acids, and methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid as organic acids (maleic acid), succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid (gluconic acid), galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc. can be used. , but not limited to these.
- a pharmaceutically acceptable metal salt can be prepared using a base.
- the alkali metal salt or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate.
- it is pharmaceutically suitable to prepare a sodium, potassium, or calcium salt as the metal salt, but is not limited thereto.
- the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).
- Pharmaceutically acceptable salts of the compounds of the present invention include salts of acidic or basic groups that may be present in the compound of Formula 1 above.
- pharmaceutically acceptable salts may include sodium, calcium and potassium salts of a hydroxyl group
- other pharmaceutically acceptable salts of an amino group include hydrobromide, sulfate, hydrogen sulfate, phosphate, and hydrogen phosphate.
- the salt of the compound of Formula 1 of the present invention is a pharmaceutically acceptable salt, and exhibits pharmacological activity equivalent to that of the compound of Formula 1, for example, a salt of the compound of Formula 1 that inhibits aggregation and/or hyperphosphorylation of tau protein All of them can be used without any restrictions.
- the compound represented by Formula 1 according to the present invention includes, without limitation, not only pharmaceutically acceptable salts thereof, but also solvates such as hydrates and all possible stereoisomers that can be prepared therefrom. Solvates and stereoisomers of the compound represented by Formula 1 may be prepared from the compound represented by Formula 1 using methods known in the art.
- the compound represented by Formula 1 according to the present invention may be prepared in a crystalline form or an amorphous form, and when prepared in a crystalline form, may be optionally hydrated or solvated.
- compounds containing various amounts of water as well as stoichiometric hydrates of the compound represented by Formula 1 may be included.
- the solvate of the compound represented by Formula 1 according to the present invention includes both stoichiometric solvates and non-stoichiometric solvates.
- a second aspect of the present invention provides a method for preparing a compound represented by Formula 1 above.
- the compound of the present invention may be prepared by reacting a compound represented by the following Chemical Formula 2 containing a reactive amine group at one end with sodium nitrite and malononitrile in the presence of an acid to form an imine bond; and
- R 1 when R 1 is a substituent other than hydrogen, it may be prepared by a process, further comprising a second step of introducing a R 1 substituent into the product obtained from the previous step:
- L, (Het)Ar 1 and (Het)Ar 2 and R 1 are as defined in the first aspect.
- the first step of the process is
- Step 1-1 of dissolving the compound of Formula 2 and sodium nitrite in a C 1-4 lower alcohol solvent, and adding an aqueous acid solution at -5 to 5° C. to form a diazonium salt;
- Step 1-2 in which malononitrile is added to the reaction solution containing the diazonium salt obtained from Step 1-1 and reacted at 15 to 40° C.
- steps 1-3 of neutralization may be carried out by a series of processes including steps 1-3 of neutralization by adding an aqueous base solution to the reaction solution of steps 1-2, but is not limited thereto.
- step 1-1 the reaction of step 1-1 is performed at a low temperature near 0° C. for 2 minutes to 1 hour using a 1M hydrochloric acid solution, and then, steps 1-2 for 2 minutes to 1 hour at room temperature.
- the reaction of the steps may be carried out, but is not limited thereto.
- the second step may be performed by reacting the carbonohydrazonoyl dicyanide compound in which R 1 obtained from the previous step is not substituted with a halogenated derivative of R 1 in an organic solvent.
- R 1 is C 1-6 alkyl
- the reaction may be carried out by adding alkane iodide to the reaction solution at 50 to 70° C., and the reaction solution may further include potassium tert-butoxide, but is not limited thereto.
- R 1 is C 1-6 alkylcarbonyl
- R 1 to the one obtained from the previous step was dissolved hydroxy carboxylic Bono unsubstituted rajo Russo dish cyanide compound in a lower alcohol such as methanol, for example a base, potassium hydroxide and After the reaction, the product obtained by solidification may be reacted with a halogenated alkylcarbonyl corresponding to C 1-6 alkylcarbonyl, for example, acetyl chloride, in the presence of triethylamine in an organic solvent such as acetonitrile, but is not limited thereto. does not
- the compound represented by Formula 2 including a reactive amine group at one end used in the preparation of the compound of the present invention, is prepared from a compound represented by the following Formula 3 having a nitro group in the reactive amine group through a reduction reaction can be, but is not limited to:
- the reduction may be carried out in an organic solvent such as 1,4-dioxane or methanol under a Pd/C catalyst, by reacting with AcOH in the presence of Fe, or by reacting with ammonium chloride in the presence of Fe, but not limited
- (Het)Ar 1 and (Het)Ar 2 any one of a carboxylic acid derivative is dissolved in an organic solvent, MeCN, or ACN, and then HATU and TEA are added or the reaction prepared by stirring it at room temperature for several hours. It may be prepared by adding another amine derivative of (Het)Ar 1 and (Het)Ar 2 to the solution and refluxing for 12 to 48 hours, but is not limited thereto.
- (Het)Ar 1 and (Het)Ar 2 any one of a carboxylic acid derivative is dissolved in an organic solvent, anhydrous DCM, and then added (COCl) 2 and a small amount of DMF at 0 °C 1 hour After concentration under reduced pressure by stirring, the other one of (Het)Ar 1 and (Het)Ar 2 is dissolved in the concentrate, an organic solvent, and pyridine, and stirred at room temperature for 3 to 24 hours. It is not limited thereto.
- the reaction temperature is lowered to a low temperature close to 0° C. and sodium hydride is added thereto for several to several tens of minutes.
- It can be prepared by adding another halosulfonyl of (Het)Ar 1 and (Het)Ar 2 , for example, a sulfonyl chloride derivative, to the reaction solution prepared by stirring and stirring at room temperature for 1 to 12 hours, but limited thereto. doesn't happen
- the reactants and/or precursors used in each step in the preparation method of the present invention may be purchased and used with commercially available compounds, or through a single reaction known in the art by purchasing the reactants or intermediates of each step or It can be synthesized by combining several reactions, but is not limited thereto.
- a process of isolating and/or purifying the product may be further included, if necessary, and this may be performed using various methods known in the art.
- a third aspect of the present invention provides a composition for inhibiting tau protein aggregation comprising the compound of the present invention as an active ingredient.
- a fourth aspect of the present invention provides a composition for inhibiting tau protein hyperphosphorylation comprising the compound of the present invention as an active ingredient.
- a fifth aspect of the present invention provides a pharmaceutical composition for preventing or treating diseases caused by aggregation or hyperphosphorylation of tau protein comprising the compound of the present invention as an active ingredient.
- a sixth aspect of the present invention provides a method for preventing or treating a disease caused by aggregation or hyperphosphorylation of tau protein, comprising administering a compound of the present invention to an individual in need thereof.
- prevention refers to any action that inhibits or delays the occurrence, spread, and recurrence of a disease induced by aggregation or hyperphosphorylation of tau protein by administration of the pharmaceutical composition of the present invention
- treatment means any action in which the symptoms of the disease are improved or advantageously changed by administration of the pharmaceutical composition of the present invention.
- the compound of the present invention not only inhibits the aggregation or hyperphosphorylation of tau protein, but also does not exhibit toxicity to cells, so the pharmaceutical composition comprising it as an active ingredient is caused by aggregation or hyperphosphorylation of tau protein It can be used for the prevention or treatment of diseases.
- Diseases caused by aggregation or hyperphosphorylation of tau protein to which the pharmaceutical composition of the present invention can be applied are Alzheimer's disease, Parkinson's disease, vascular dementia, acute stroke, trauma, cerebrovascular disease, brain cord trauma, spinal cord trauma, peripheral neuropathy, retinopathy, glaucoma or tauopathies.
- Non-limiting examples of such tauopathy include chronic traumatic encephalopathy (CTE), primary age-related tauopathy, progressive supranuclear palsy, corticobasal degeneration. , Pick's disease, argyrophilic grain disease (AGD), frontotemporal dementia (FTD), Parkinsonism linked to chromosome 17, Lytico-Bodig disease ( Lytico-Bodig disease, Parkinson-dementia complex of Guam, ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Pantothenate kinase-associated neurodegeneration, lipofuscinosis, posttraumatic stress disorder, and traumatic brain injury.
- CTE chronic traumatic encephalopathy
- ATD argyrophilic grain disease
- FTD frontotemporal dementia
- Parkinsonism linked to chromosome 17 Lytic
- composition of the present invention may further include a pharmaceutically acceptable carrier, diluent or excipient, and may be powder, granule, tablet, capsule, suspension, emulsion, It can be formulated and used in various forms such as oral formulations such as syrup and aerosol, injections of sterile injection solutions, etc. .
- compositions examples include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, and cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil.
- the composition of the present invention may further include a filler, an anti-agglomeration agent, a lubricant, a wetting agent, a fragrance, an emulsifier, a preservative, and the like.
- Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations include at least one excipient in the composition, for example, starch, calcium carbonate, sucrose, lactose, gelatin, etc. are mixed and formulated.
- excipients for example, starch, calcium carbonate, sucrose, lactose, gelatin, etc.
- lubricants such as magnesium stearate and talc may be used.
- Liquid formulations for oral use may include suspensions, solutions, emulsions, syrups, etc., and various excipients, such as wetting agents, sweeteners, fragrances, preservatives, etc., in addition to water and liquid paraffin, which are commonly used simple diluents, may be included.
- excipients such as wetting agents, sweeteners, fragrances, preservatives, etc., in addition to water and liquid paraffin, which are commonly used simple diluents, may be included.
- Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations, and suppositories.
- Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
- the suppositories are Witepsol, Macrogol, and Twin61. Cacao butter, laurin fat, glycerogelatin, etc. may be used.
- the injection may contain conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, preservatives, and the like.
- the formulation may be prepared by a conventional mixing, granulating or coating method and may contain the active ingredient in the range of about 0.1 to 75% by weight, preferably about 1 to 50% by weight.
- a unit dosage form for a mammal weighing about 50 to 70 kg contains about 10 to 200 mg of active ingredient.
- the composition of the present invention is administered in a pharmaceutically effective amount.
- pharmaceutically effective amount refers to an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and not to cause side effects, and the effective dose level depends on the patient's health condition, disease type, severity, drug activity, sensitivity to drug, administration method, administration time, administration route and excretion rate, duration of treatment, factors including drugs used in combination or concomitantly, and other factors well known in the medical field.
- the composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. In consideration of all of the above factors, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, which can be easily determined by those skilled in the art.
- the dosage may be increased or decreased according to the route of administration, disease severity, sex, weight, age, etc., and thus the dosage is not intended to limit the scope of the present invention in any way.
- the preferred dosage of the compound of the present invention varies depending on the condition and weight of the patient, the severity of the disease, the form of the drug, the route and duration of administration, but may be appropriately selected by those skilled in the art. However, for a desirable effect, it is preferable to administer the compound of the present invention at 0.0001 to 100 mg/kg (body weight), preferably 0.001 to 100 mg/kg (body weight) per day. Administration may be administered once a day or in divided doses via oral or parenteral routes.
- a seventh aspect of the present invention provides a method for preventing or treating a disease caused by aggregation or hyperphosphorylation of tau protein, comprising administering the pharmaceutical composition of the present invention to an individual in need thereof.
- the term "individual” means monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, including humans, that have invented or can develop diseases caused by aggregation or hyperphosphorylation of tau protein. , refers to all animals, including mice, rats, rabbits or guinea pigs, and can effectively prevent or treat the disease by administering the pharmaceutical composition of the present invention to an individual.
- the pharmaceutical composition of the present invention since the pharmaceutical composition of the present invention exhibits a therapeutic effect by inhibiting aggregation or hyperphosphorylation of tau protein, it may exhibit a synergistic effect by administering in parallel with a conventional therapeutic agent.
- administration means providing a predetermined substance to a patient by any suitable method, and the administration route of the composition of the present invention may be administered through any general route as long as it can reach the target tissue.
- Intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, intrapulmonary administration may be administered intrarectally, but is not limited thereto.
- the pharmaceutical composition of the present invention may be administered by any device capable of transporting an active substance to a target cell.
- Preferred administration modes and formulations are intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, drip injections, and the like.
- aqueous solvents such as physiological saline solution and Ringel's solution, vegetable oil, higher fatty acid esters (eg, ethyl oleate), and non-aqueous solvents such as alcohols (eg, ethanol, benzyl alcohol, propylene glycol, glycerin, etc.)
- Stabilizers for preventing deterioration e.g., ascorbic acid, sodium hydrogen sulfite, sodium pyrosulfite, BHA, tocopherol, EDTA, etc.
- emulsifiers e.g., buffers for pH adjustment, to inhibit the growth of microorganisms
- Pharmaceutical carriers such as preservatives (eg, phenylmercuric nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.) may be included.
- Step 1-1 Preparation of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide
- Step 1-2 Preparation of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide
- Step 1-3 Preparation of (6-(5-methylpyrazine-2-carboxamido)pyridin-3-yl)carbonohydrazonoyl dicyanide
- N- (5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide (40 mg, 0.17 mmol) and sodium nitrite (18 mg, 0.26 mmol) obtained from step 1-2 above under nitrogen was dissolved in ethanol, and 1.0 M aqueous hydrochloric acid solution (0.5 mL, 0.52 mmol) was added at 0°C.
- the reaction mixture was stirred at 0° C. for 10 minutes to form a diazonium salt.
- malononitrile 23 mg, 0.35 mmol
- Step 2-1 Preparation of 5-methyl-N-(4-nitrophenyl)pyrazine-2-carboxamide
- Step 2-2 Preparation of N-(4-aminophenyl)-5-methylpyrazine-2-carboxamide
- Step 2-3 Preparation of (4-(5-methylpyrazine-2-carboxamido)phenyl)carbonohydrazonoyl dicyanide
- Step 3-1 Preparation of N-(3-fluoro-4-nitrophenyl)-5-methylpyrazine-2-carboxamide
- Step 3-2 Preparation of N-(4-amino-3-fluorophenyl)-5-methylpyrazine-2-carboxamide
- Step 3-3 Preparation of (2-fluoro-4-(5-methylpyrazine-2-carboxamido)phenyl)carbonohydrazonoyl dicyanide
- Step 4-1 Preparation of N-(3-methoxy-4-nitrophenyl)-5-methylpyrazine-2-carboxamide
- Step 4-2 Preparation of N-(4-amino-3-methoxyphenyl)-5-methylpyrazine-2-carboxamide
- Step 4-3 Preparation of (2-methoxy-4-(5-methylpyrazine-2-carboxamido)phenyl)carbonohydrazonoyl dicyanide
- Step 5-1 Preparation of N-(3-chloro-4-nitrophenyl)-5-methylpyrazine-2-carboxamide
- Step 5-2 Preparation of N-(4-amino-3-chlorophenyl)-5-methylpyrazine-2-carboxamide
- Step 5-3 Preparation of (2-chloro-4- (5-methylpyrazine-2-carboxamido) phenyl) carbonohydrazonoyl dicyanide
- Step 6-1 Preparation of 5-methyl-N-(3-methyl-4-nitrophenyl)pyrazine-2-carboxamide
- Step 6-2 Preparation of N-(4-amino-3-methylphenyl)-5-methylpyrazine-2-carboxamide
- Step 6-3 Preparation of (2-methyl-4-(5-methylpyrazine-2-carboxamido)phenyl)carbonohydrazonoyl dicyanide
- Step 7-1 Preparation of N-(2-fluoro-4-nitrophenyl)-5-methylpyrazine-2-carboxamide
- Step 7-2 Preparation of N-(4-amino-2-fluorophenyl)-5-methylpyrazine-2-carboxamide
- Step 7-3 Preparation of (3-fluoro-4-(5-methylpyrazine-2-carboxamido)phenyl)carbonohydrazonoyl dicyanide
- Step 8-1 Preparation of 5-methyl-N-(2-methyl-4-nitrophenyl)pyrazine-2-carboxamide
- Step 8-2 Preparation of N-(4-amino-2-methylphenyl)-5-methylpyrazine-2-carboxamide
- Step 8-3 Preparation of (3-methyl-4-(5-methylpyrazine-2-carboxamido)phenyl)carbonohydrazonoyl dicyanide
- Example 8 (3-methyl-4-(5-methylpyrazine-2-carboxamido)phenyl)carbonohydrazonoyl dicyanide (100 mg, 0.31 mmol) obtained in Example 8 was mixed with dimethylformamide (DMF) ), potassium tert-butoxide (46 mg, 0.41 mmol) was added at room temperature, and then methane iodide (39 ⁇ L, 0.63 mmol) was added. The reaction mixture was stirred at 60° C. for 12 h. Upon completion of the reaction, extraction was performed with distilled water and ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain 4 mg (yield 3%) of the title compound.
- DMF dimethylformamide
- methane iodide 39 ⁇ L, 0.63 mmol
- Step 10-1 Preparation of N-(2-methoxy-4-nitrophenyl)-5-methylpyrazine-2-carboxamide
- Step 10-2 Preparation of N-(4-amino-2-methoxyphenyl)-5-methylpyrazine-2-carboxamide
- Step 10-3 Preparation of (3-methoxy-4-(5-methylpyrazine-2-carboxamido)phenyl)carbonohydrazonoyl dicyanide
- Step 11-1 Preparation of N-(2-chloro-4-nitrophenyl)-5-methylpyrazine-2-carboxamide
- Step 11-2 Preparation of N-(4-amino-2-chlorophenyl)-5-methylpyrazine-2-carboxamide
- Step 11-3 Preparation of (3-chloro-4-(5-methylpyrazine-2-carboxamido)phenyl)carbonohydrazonoyl dicyanide
- Step 12-1 Preparation of 5-methyl-N-(3-methyl-5-nitropyridin-2-yl)pyrazine-2-carboxamide
- Step 12-2 Preparation of N-(5-amino-3-methylpyridin-2-yl)-5-methylpyrazine-2-carboxamide
- Step 12-3 Preparation of (5-methyl-6-(5-methylpyrazine-2-carboxamido)pyridin-3-yl)carbonohydrazonoyl dicyanide
- Step 13-1 Preparation of 5-methyl-N-(4-methyl-5-nitropyridin-2-yl)pyrazine-2-carboxamide
- Step 13-2 Preparation of N-(5-amino-4-methylpyridin-2-yl)-5-methylpyrazine-2-carboxamide
- Step 13-3 Preparation of (4-methyl-6-(5-methylpyrazine-2-carboxamido)pyridin-3-yl)carbonohydrazonoyl dicyanide
- Step 14-1 Preparation of 5-methyl-N-(6-nitropyridin-3-yl)pyrazine-2-carboxamide
- Step 14-2 Preparation of N-(6-aminopyridin-3-yl)-5-methylpyrazine-2-carboxamide
- Step 14-3 Preparation of (5-(5-methylpyrazine-2-carboxamido)pyridin-2-yl)carbonohydrazonoyl dicyanide
- Step 15-3 Preparation of (6-benzamidopyridin-3-yl)carbonohydrazonoyl dicyanide
- Step 16-1 Preparation of 4-fluoro-N-(5-nitropyridin-2-yl)benzamide
- Step 16-2 Preparation of N-(5-aminopyridin-2-yl)-4-fluorobenzamide
- Step 16-3 Preparation of (6-(4-fluorobenzamido)pyridin-3-yl)carbonohydrazonoyl dicyanide
- Step 17-1 Preparation of 2-fluoro-N-(5-nitropyridin-2-yl)benzamide
- Step 17-2 Preparation of N-(5-aminopyridin-2-yl)-2-fluorobenzamide
- Step 17-3 Preparation of (6-(2-fluorobenzamido)pyridin-3-yl)carbonohydrazonoyl dicyanide
- Step 18-1 Preparation of 3-fluoro-N-(5-nitropyridin-2-yl)benzamide
- Step 18-2 Preparation of N-(5-aminopyridin-2-yl)-3-fluorobenzamide
- Step 18-3 Preparation of (6-(3-fluorobenzamido)pyridin-3-yl)carbonohydrazonoyl dicyanide
- Step 19-1 Preparation of 3-fluoro-5-methyl-N-(5-nitropyridin-2-yl)benzamide
- Step 19-2 Preparation of N-(5-aminopyridin-2-yl)-3-fluoro-5-methylbenzamide
- Step 19-3 Preparation of (6-(3-fluoro-5-methylbenzamido)pyridin-3-yl)carbonohydrazonoyl dicyanide
- Step 20-1 Preparation of 2-fluoro-3-methyl-N-(5-nitropyridin-2-yl)benzamide
- Step 20-2 Preparation of N-(5-aminopyridin-2-yl)-2-fluoro-3-methylbenzamide
- Step 20-3 Preparation of (6-(2-fluoro-3-methylbenzamido)pyridin-3-yl)carbonohydrazonoyl dicyanide
- Step 21-1 Preparation of 4-fluoro-3-methyl-N-(5-nitropyridin-2-yl)benzamide
- Step 21-2 Preparation of N-(5-aminopyridin-2-yl)-4-fluoro-3-methylbenzamide
- Step 21-3 Preparation of (6-(4-fluoro-3-methylbenzamido)pyridin-3-yl)carbonohydrazonoyl dicyanide
- Step 22-1 Preparation of 3-fluoro-4-methyl-N-(5-nitropyridin-2-yl)benzamide
- Step 22-3 Preparation of (6-(3-fluoro-4-methylbenzamido)pyridin-3-yl)carbonohydrazonoyl dicyanide
- Step 23-3 Preparation of (6-(4-methylbenzamido)pyridin-3-yl)carbonohydrazonoyl dicyanide
- Step 24-1 Preparation of 3-methyl-N-(5-nitropyridin-2-yl)benzamide
- Step 24-3 Preparation of (6-(3-methylbenzamido)pyridin-3-yl)carbonohydrazonoyl dicyanide
- Step 25-1 Preparation of 2-methyl-N-(5-nitropyridin-2-yl)benzamide
- Step 25-2 Preparation of N-(5-aminopyridin-2-yl)-2-methylbenzamide
- Step 25-3 Preparation of (6-(2-methylbenzamido)pyridin-3-yl)carbonohydrazonoyl dicyanide
- Step 26-1 Preparation of N-(5-nitropyridin-2-yl)-3-(trifluoromethyl)benzamide
- Step 26-2 Preparation of N-(5-aminopyridin-2-yl)-3-(trifluoromethyl)benzamide
- Step 26-3 Preparation of (6-(3-(trifluoromethyl)benzamido)pyridin-3-yl)carbonohydrazonoyl dicyanide
- Step 27-1 Preparation of N-(5-nitropyridin-2-yl)-4-(trifluoromethyl)benzamide
- Step 27-2 Preparation of N-(5-aminopyridin-2-yl)-4-(trifluoromethyl)benzamide
- Step 27-3 Preparation of (6-(4-(trifluoromethyl)benzamido)pyridin-3-yl)carbonohydrazonoyl dicyanide
- Step 28-1 Preparation of N-(5-nitropyridin-2-yl)-2-(trifluoromethyl)benzamide
- Step 28-2 Preparation of N-(5-aminopyridin-2-yl)-2-(trifluoromethyl)benzamide
- Step 28-3 Preparation of (6-(4-(trifluoromethyl)benzamido)pyridin-3-yl)carbonohydrazonoyl dicyanide
- Step 29-1 Preparation of N-(5-nitropyridin-2-yl)pyrimidine-2-carboxamide
- Step 29-2 Preparation of N-(5-aminopyridin-2-yl)pyrimidine-2-carboxamide
- Step 29-3 Preparation of (6-(pyrimidine-2-carboxamido)pyridin-3-yl)carbonohydrazonoyl dicyanide
- Step 30-1 Preparation of N-(5-nitropyridin-2-yl)thiophene-2-carboxamide
- Step 30-2 Preparation of N-(5-aminopyridin-2-yl)thiophene-2-carboxamide
- Step 30-3 Preparation of (6-(thiophene-2-carboxamido)pyridin-3-yl)carbonohydrazonoyl dicyanide
- Step 31-1 N-(5-nitropyridin-2-yl)benzo[ d ] Preparation of thiazole-2-carboxamide
- Step 31-2 N-(5-aminopyridin-2-yl)benzo[ d ] Preparation of thiazole-2-carboxamide
- Step 31-3 Preparation of (6-(benzo [d] thiazole-2-carboxamido) pyridin-3-yl) carbonohydrazonoyl dicyanide
- Step 32-1 Preparation of N-(5-nitropyridin-2-yl)quinoxaline-2-carboxamide
- Step 32-2 Preparation of N-(5-aminopyridin-2-yl)quinoxaline-2-carboxamide
- Step 32-3 Preparation of (6-(quinoxaline-2-carboxamido)pyridin-3-yl)carbonohydrazonoyl dicyanide
- Step 33-1 Preparation of 5-methyl-N-(6-nitrothiazolo[4,5-b]pyridin-2-yl)pyrazine-2-carboxamide
- Step 33-2 Preparation of N-(6-aminothiazolo[4,5-b]pyridin-2-yl)-5-methylpyrazine-2-carboxamide
- Step 33-3 Preparation of (2-(5-methylpyrazine-2-carboxamido)thiazolo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide
- Step 34-3 Preparation of (6-(p-tolylcarbamoyl)pyridin-3-yl)carbonohydrazonoyl dicyanide
- Step 35-1 Preparation of N-(4-methoxyphenyl)-5-nitropicolinamide
- Step 35-3 Preparation of (6-(4-methoxyphenylcarbamoyl)pyridin-3-yl)carbonohydrazonoyl dicyanide
- Step 36-1 Preparation of N-(5-methylpyrazin-2-yl)-5-nitropicolinamide
- Step 36-2 Preparation of 5-amino-N-(5-methylpyrazin-2-yl)picolinamide
- Step 36-3 Preparation of (6-(5-methylpyrazin-2-ylcarbamoyl)pyridin-3-yl)carbonohydrazonoyl dicyanide
- Step 37-1 Preparation of N-(4-chlorophenyl)-5-nitropicolinamide
- Step 37-2 Preparation of 5-amino-N-(4-chlorophenyl)picolinamide
- N- (4-chlorophenyl)-5-nitropicolinamide (267 mg, 0.96 mmol) obtained from step 37-1 above was used instead of DMF as a solvent. Except for using 1,4-dioxane, the reaction was carried out in a manner similar to step 34-2 of Example 34, to obtain 174 mg (yield 73%) of the title compound.
- Step 37-3 Preparation of (6-(4-chlorophenylcarbamoyl)pyridin-3-yl)carbonohydrazonoyl dicyanide
- Step 38-1 Preparation of N-(6-methylpyridin-3-yl)-5-nitropicolinamide
- Step 38-2 Preparation of 5-amino-N-(6-methylpyridin-3-yl)picolinamide
- Step 38-3 Preparation of (6-(6-methylpyridin-3-ylcarbamoyl)pyridin-3-yl)carbonohydrazonoyl dicyanide
- Step 39-1 Preparation of N-(5-methylpyridin-3-yl)-5-nitropicolinamide
- Step 39-2 Preparation of 5-amino-N-(5-methylpyridin-3-yl)picolinamide
- Step 39-3 Preparation of (6-(5-methylpyridin-3-ylcarbamoyl)pyridin-3-yl)carbonohydrazonoyl dicyanide
- Step 40-1 Preparation of 5-nitro-N-(pyridin-3-yl)picolinamide
- Step 40-2 Preparation of 5-amino-N-(pyridin-3-yl)picolinamide
- Step 40-3 Preparation of (6-(pyridin-3-ylcarbamoyl)pyridin-3-yl)carbonohydrazonoyl dicyanide
- Step 41-1 Preparation of N-(6-methylpyrazin-2-yl)-5-nitropicolinamide
- Step 41-2 Preparation of 5-amino-N-(6-methylpyrazin-2-yl)picolinamide
- Step 41-3 Preparation of (6-(6-methylpyrazin-2-ylcarbamoyl)pyridin-3-yl)carbonohydrazonoyl dicyanide
- Step 42-3 Preparation of (6-(pyrimidin-5-ylcarbamoyl)pyridin-3-yl)carbonohydrazonoyl dicyanide
- Step 43-3 Preparation of (6-(pyrimidin-2-ylcarbamoyl)pyridin-3-yl)carbonohydrazonoyl dicyanide
- Example 34 The steps of Example 34 above, except that 4-nitrobenzoic acid (200 mg, 1.20 mmol) was used instead of 5-nitrocholic acid and p-anisidine (147 mg, 1.20 mmol) was used instead of p-toluidine.
- the reaction was carried out in a similar manner to 34-1 to obtain 174 mg (yield 53%) of the title compound.
- Step 44-2 Preparation of 4-amino-N-(4-methoxyphenyl)benzamide
- Step 44-3 Preparation of (4-(4-methoxyphenylcarbamoyl)phenyl)carbonohydrazonoyl dicyanide
- Step 45-3 Preparation of (4-(5-methylpyrazin-2-ylcarbamoyl)phenyl)carbonohydrazonoyl dicyanide
- Step 46-2 Preparation of 4-amino-N-(6-methylpyrazin-2-yl)benzamide
- Step 46-3 Preparation of (4-(6-methylpyrazin-2-ylcarbamoyl)phenyl)carbonohydrazonoyl dicyanide
- Step 47-3 Preparation of (4-(6-methylpyridin-3-ylcarbamoyl)phenyl)carbonohydrazonoyl dicyanide
- Step 48-1 Preparation of N-(5-methylpyridin-3-yl)-4-nitrobenzamide
- Step 48-2 Preparation of 4-amino-N-(5-methylpyridin-3-yl)benzamide
- Step 48-3 Preparation of (4-(5-methylpyridin-3-ylcarbamoyl)phenyl)carbonohydrazonoyl dicyanide
- Step 49-3 Preparation of (4-(pyridin-3-ylcarbamoyl)phenyl)carbonohydrazonoyl dicyanide
- Step 50-2 Preparation of 4-amino-N-(pyrimidin-5-yl)benzamide
- Step 50-3 Preparation of (4-(pyrimidin-5-ylcarbamoyl)phenyl)carbonohydrazonoyl dicyanide
- Step 51-1 Preparation of 3-methoxy-N-(5-methylpyrazin-2-yl)-4-nitrobenzamide
- Step 51-2 Preparation of 4-amino-3-methoxy-N-(5-methylpyrazin-2-yl)benzamide
- Step 51-3 Preparation of (2-methoxy-4-(5-methylpyrazin-2-ylcarbamoyl)phenyl)carbonohydrazonoyl dicyanide
- Step 52-2 Preparation of 4-amino-2-methyl-N-(5-methylpyrazin-2-yl)benzamide
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Abstract
Description
실시예 | 실시예 | ||
1 | 2 | ||
3 | 4 | ||
5 | 6 | ||
7 | 8 | ||
9 | 10 | ||
11 | 12 | ||
13 | 14 | ||
15 | 16 | ||
17 | 18 | ||
19 | 20 | ||
21 | 22 | ||
23 | 24 | ||
25 | 26 | ||
27 | 28 | ||
29 | 30 | ||
31 | 32 | ||
33 | 34 | ||
35 | 36 | ||
37 | 38 | ||
39 | 40 | ||
41 | 42 | ||
43 | 44 | ||
45 | 46 | ||
47 | 48 | ||
49 | 50 | ||
51 | 52 | ||
53 | 54 | ||
55 | 56 | ||
57 | 58 | ||
59 | 60 | ||
61 | 62 | ||
63 | 64 | ||
65 | 66 | ||
67 | 68 | ||
69 | 70 | ||
71 | 72 | ||
73 | 74 | ||
75 | 76 | ||
77 | 78 | ||
79 | 80 | ||
81 | 82 | ||
83 | 84 | ||
85 | 86 | ||
87 | 88 | ||
89 | 90 | ||
91 | 92 | ||
93 | 94 | ||
95 | 96 | ||
97 | 98 | ||
99 | 100 | ||
101 | 102 | ||
103 | 104 | ||
105 | 106 | ||
107 | 108 | ||
109 | 110 | ||
111 | 112 | ||
113 | 114 | ||
115 | 116 | ||
117 | 118 | ||
119 | 120 | ||
121 | 122 | ||
123 | 124 | ||
125 | 126 | ||
127 | 128 | ||
129 | 130 | ||
131 | 132 | ||
133 | 134 | ||
135 | 136 | ||
137 | 138 | ||
139 | 140 | ||
141 | 142 | ||
143 | 144 | ||
145 | 146 | ||
147 | 148 | ||
149 | 150 | ||
151 | 152 | ||
153 | 154 | ||
155 | 156 | ||
157 | 158 | ||
159 | 160 | ||
161 | 162 | ||
163 | 164 | ||
165 | 166 | ||
167 | 168 | ||
169 | 170 | ||
171 | 172 | ||
173 | 174 | ||
175 |
화합물 # |
Tau BiFC in cells | ||
IC50
(μM) |
Response (% @10 μM) |
세포 생존율 (% @10 μM) |
|
1 | 0.4 | 0 | 94.3 |
2 | 1.4 | 0 | 71.5 |
3 | 0.03 | 0 | 62.1 |
4 | - | 30.7 | 67 |
5 | - | 14.5 | 61.2 |
6 | - | 43.9 | 61.3 |
7 | - | 0 | 30.6 |
8 | 0.04 | 0 | 88 |
10 | - | 0 | 21.7 |
11 | 0.11 | 0 | 82.5 |
12 | 0.64 | 17.9 | 122.1 |
13 | 0.55 | 30 | 110 |
14 | - | 147.4 | 102 |
15 | 0.09 | 0 | 79.9 |
16 | 0.11 | 0 | 66.2 |
17 | 0.31 | 0 | 102.7 |
18 | 0.66 | 0 | 113 |
19 | 0.27 | 0 | 119.1 |
20 | 0.18 | 0 | 110.4 |
21 | 0.75 | 0 | 104.3 |
22 | 0.32 | 0 | 105.8 |
23 | 0.13 | 0 | 114.2 |
24 | <0.30 | 0 | 103.9 |
25 | 0.39 | 0 | 122.4 |
26 | 0.71 | 0 | 109.8 |
27 | 0.37 | 0 | 122 |
28 | 0.54 | 0 | 125.8 |
29 | 1.04 | 0 | 139.9 |
30 | 0.08 | 0 | 145 |
31 | 0.54 | 0 | 114.3 |
32 | 0.31 | 0 | 145.3 |
33 | - | 63.9 | 125 |
34 | 9 | 76 | 88.1 |
35 | - | 34.2 | 97.9 |
36 | - | 35.9 | 86.9 |
37 | - | 62.7 | 117.8 |
38 | 0.99 | 0 | 110.6 |
39 | 0.63 | 0 | 131.1 |
40 | - | 7.9 | 130.7 |
41 | - | 0 | 115.2 |
42 | - | 0 | 123.1 |
43 | - | 3 | 168.6 |
44 | - | 0 | 70.4 |
45 | 1.18 | 0 | 140.5 |
46 | 0.86 | 0 | 155 |
47 | 2.58 | 0 | 122.7 |
48 | - | 0 | 122.3 |
49 | - | 75.9 | 117.2 |
50 | - | 86.6 | 116.4 |
51 | - | 45.4 | 107.1 |
52 | - | 24 | 120.2 |
53 | - | 22.9 | 116.1 |
54 | - | 8.3 | 116 |
55 | - | 65.6 | 116.1 |
56 | 1.85 | 0 | 129.9 |
57 | - | 51.7 | 108.6 |
58 | - | 51.4 | 113.5 |
59 | - | 74.3 | 128.2 |
60 | - | 90.2 | 116.9 |
61 | - | 108.8 | 112.7 |
62 | - | 87.3 | 116.5 |
63 | - | 11.5 | 136.7 |
64 | - | 56 | 114.2 |
65 | - | 72.6 | 111.4 |
66 | - | 61.2 | 123.9 |
67 | - | 68.2 | 108.4 |
68 | 0.11 | 0 | 117 |
69 | 0.26 | 0 | 119.4 |
70 | 0.31 | 0 | 94.5 |
71 | - | 0 | 46 |
72 | 1.99 | 0 | 129.5 |
73 | - | 0 | 49.6 |
74 | 0.44 | 0 | 92.7 |
75 | - | 102.3 | 131.4 |
76 | - | 79.9 | 121.7 |
77 | - | 84.8 | 91.6 |
78 | - | 69.6 | 74 |
79 | - | 65.9 | 115.7 |
80 | - | 68 | 112.3 |
81 | 0.55 | 0 | 116.2 |
82 | 2.96 | 0 | 126.4 |
83 | 1.14 | 0 | 104 |
84 | 2.12 | 0 | 111.4 |
85 | 1.58 | 0 | 99.1 |
86 | 2.12 | 0 | 72.6 |
87 | 1.22 | 0 | 39.4 |
88 | 3.06 | 0 | 44.4 |
89 | 2.4 | 0 | 32.5 |
90 | 1.29 | 0 | 43.7 |
91 | 3.12 | 0 | 117 |
92 | 0.55 | 0 | 116.8 |
93 | 1.29 | 0 | 66.5 |
94 | 1.28 | 0 | 33.6 |
95 | - | 0 | 71.9 |
96 | 0.4 | 0 | 27.5 |
97 | 0.1 | 0 | 27.1 |
98 | 0.25 | 0 | 26.9 |
99 | 0.24 | 0 | 29.2 |
100 | 0.78 | 0 | 39.4 |
101 | 0.95 | 0 | 30.1 |
102 | 0.96 | 0 | 54.5 |
103 | 2.35 | 0 | 37.9 |
104 | 0.26 | 0 | 142 |
105 | 0.4 | 0 | 142.9 |
106 | - | 0 | 184.9 |
107 | 0.6 | 0 | 137.9 |
108 | 1.4 | 0 | 121.8 |
109 | 1.4 | 0 | 141.8 |
110 | 0.79 | 0 | 160.5 |
111 | 0.5 | 0 | 136.4 |
112 | 0.2 | 0 | 158.2 |
113 | 0.2 | 0 | 147 |
114 | 1.5 | 0 | 149.5 |
115 | 0.6 | 0 | 157.6 |
116 | 1.4 | 0 | 124 |
117 | 1.24 | 16.6 | 126.0 |
118 | 5.75 | 25.7 | 82.6 |
119 | 3.55 | 38.9 | 112.5 |
120 | 1.45 | 0.0 | 66.2 |
121 | 4.61 | 3.4 | 72.7 |
122 | 1.86 | 11.7 | 92.9 |
123 | 0.78 | 0.0 | 34.6 |
124 | 0.62 | 0.0 | 140.9 |
125 | 2.3 | 0.0 | 140.5 |
126 | 0.1 | 0.0 | 133.2 |
127 | 1.2 | 0.0 | 134.9 |
128 | 0.3 | 0.0 | 108.5 |
129 | 0.2 | 0.0 | 106.9 |
130 | - | 0.0 | 113 |
131 | - | 10.6 | 33.4 |
132 | - | 0.0 | 39.2 |
133 | - | 0.0 | 39.7 |
134 | - | 0.0 | 38.1 |
135 | - | 0.0 | 41.7 |
136 | 1.44 | 0.0 | 95.7 |
137* | - | 31 | 129 |
138* | - | 15 | 133 |
139* | - | 39 | 123 |
140* | - | 18 | 135 |
141* | 0.866 | -25 | 109 |
142* | 1.606 | -5 | 111 |
143* | - | 11 | 125 |
144* | 1.279 | -20 | 111 |
145* | 0.126 | -49 | 95 |
146* | 0.444 | -35 | 133 |
147* | 0.147 | -19 | 98 |
148* | - | 22 | 114 |
149* | 0.185 | -8 | 124 |
150* | - | 11 | 118 |
151* | 0.022 | -32 | 126 |
152* | 0.054 | -37 | 117 |
153* | 0.037 | -43 | 122 |
154* | 0.032 | -52 | 106 |
155* | - | -43 | 80 |
156* | 0.05 | -29 | 124 |
157* | - | 8 | 124 |
158* | 0.268 | -33 | 96 |
159* | 0.007 | -40 | 114 |
160* | 0.007 | -33 | 111 |
161* | 0.109 | -17 | 119 |
162* | 0.049 | -25 | 115 |
163* | - | 91 | 106 |
164* | 0.096 | -1 | 109 |
165* | - | -40 | 113 |
166* | 0.214 | -43 | 121 |
167* | 0.01 | -38 | 118 |
168* | 0.132 | -17 | 123 |
169 | |||
170 | |||
171 | |||
172 | |||
173 | |||
174 |
시간(분) | 유속(mL/분) | %A | %B |
0 | 0.3 | 100 | 0 |
1.0 | 0.3 | 60 | 40 |
4.0 | 0.3 | 50 | 50 |
4.1 | 0.3 | 100 | 0 |
7.0 | 0.3 | 100 | 0 |
화합물 # | CYP1A2 | CYP2C9 | CYP2C19 | CYP2D6 | CYP3A4 |
1 | 80.7 | 71.1 | 74.6 | 93.1 | 85 |
3 | 85.6 | 61.9 | 78.2 | 83.6 | 80.8 |
6 | 85.2 | 38 | 64.8 | 75.7 | 62.2 |
16 | 71.4 | 40.3 | 78.6 | 80.8 | 86.9 |
19 | 55.1 | 14.6 | 73.1 | 73 | 76.5 |
20 | 69.4 | 22.3 | 72 | 75.8 | 76.1 |
23 | 85 | 40.6 | 82.5 | >100 | 83.3 |
27 | 76.8 | 23.7 | 78.3 | 76 | >100 |
30 | 83.9 | 62.9 | 81.5 | 89.9 | 95.2 |
38 | 92.5 | 49.1 | 83.0 | >100 | 92.4 |
45 | 95.5 | 80.8 | 83.4 | >100 | 96.7 |
46 | 97.8 | 70.4 | 83.1 | >100 | 85.5 |
104 | 78.4 | 48.6 | 82.4 | >100 | 66.1 |
110 | 88.3 | 77.1 | 88.4 | 91.3 | 98.9 |
124 | 23.4 | 4.4 | 69.9 | 46.6 | 37.5 |
136 | 80.3 | 70 | 76.5 | 94.4 | 88.9 |
137 | >100 | 37 | >100 | >100 | 84.8 |
138 | 97.4 | 92.5 | >100 | 92.7 | 89.4 |
140 | 96.7 | 11.7 | >100 | 69.6 | 30.8 |
143 | 95.9 | >100 | >100 | >100 | 90.3 |
144 | 37.7 | 24.5 | >100 | >100 | 89.2 |
145 | 5.3 | 2.2 | 46.5 | 39.1 | 22 |
146 | >100 | 47.2 | 88.4 | >100 | 82.7 |
151 | 51.8 | 19.4 | >100 | 94.8 | 88 |
152 | 75.5 | 17.2 | 95 | 96.1 | >100 |
153 | 67.9 | 44.1 | 100 | 90.7 | 98.9 |
154 | 79.1 | 26.6 | 76.3 | 81.7 | 72.5 |
156 | 95.9 | 54 | 83.7 | 96 | 92.6 |
159 | 42.4 | 54.7 | 88 | 86.1 | 82.1 |
160 | 5.8 | 6.5 | 68.5 | 59.7 | 17.9 |
162 | 79.8 | 73.5 | 75.9 | 70.3 | 73.3 |
화합물 # | 인간(%) | 개(%) | 랫트(%) | 마우스(%) |
1 | 86.5 | 66.9 | 56.7 | 21.2 |
3 | 95.7 | 75.4 | 72.6 | 46.1 |
6 | 77.5 | >100 | 88.4 | 74.8 |
16 | 91.6 | 59.5 | 61 | 67.3 |
19 | 84.8 | 78.8 | 51.4 | 62.3 |
20 | 91.9 | >100 | 33.7 | 68.3 |
26 | 72.5 | 29.8 | 19.8 | 7.1 |
27 | 86.9 | 3.6 | 8.8 | 5.4 |
30 | 94.8 | 84.7 | 72.4 | 70.7 |
31 | 28.7 | ND | ND | ND |
38 | 99.1 | 98.8 | >100 | 96.4 |
45 | 96.8 | >100 | >100 | >100 |
46 | >100 | >100 | 86.3 | >100 |
68 | 6.7 | 87.8 | 63 | 93.6 |
69 | 8.4 | 94.8 | 75.6 | 81.6 |
104 | 84.1 | - | 87.5 | 97.2 |
110 | 89.7 | - | 81.8 | 92.4 |
143 | 78.3 | - | 57.6 | 50 |
144 | 74.9 | - | 92.4 | 80.9 |
145 | 93.7 | - | 91.2 | 93.3 |
146 | 64.6 | - | 31.1 | 70.5 |
147 | 86.4 | - | 89 | 91.3 |
148 | 77.4 | - | 86.3 | >100 |
149 | 93.7 | - | 82.2 | 87.9 |
150 | 80.7 | - | 78.7 | 99.5 |
152 | 73.2 | - | 72.3 | 56.6 |
155 | 95.4 | - | 82 | 90.8 |
156 | 49.3 | - | 55.5 | 41.3 |
157 | 69.1 | - | 46 | 33.2 |
158 | 36.9 | - | 48.2 | 73.7 |
163 | 86.9 | - | 71.3 | 59.5 |
164 | 96.8 | - | 29.1 | 24.6 |
165 | 42.4 | - | 42.4 | 69.6 |
166 | 6.6 | - | 6.5 | 68.1 |
168 | 54.8 | - | 44 | 77.8 |
171 | 79.2 | - | 80.3 | 70.3 |
172 | 73.3 | - | 65.3 | 57.3 |
174 | 72 | - | 54.3 | >100 |
Claims (16)
- 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염:[화학식 1]상기 화학식 1에서,L은 -NHCO-, -CONH-, -NHSO2-, -SO2NH-, 또는 -(직쇄 또는 분지쇄 C0-3 알킬렌)'-O-(직쇄 또는 분지쇄 C0-3 알킬렌)"-;R1은 수소, C1-6 알킬, 또는 C1-6 알킬카보닐;(Het)Ar1은 C6-10 아릴렌 또는 5-10원 헤테로아릴렌;(Het)Ar2는 C6-10 아릴 또는 5-10원 헤테로아릴;상기 C6-10 아릴(렌) 및 5-10원 헤테로아릴(렌)은 각각 독립적으로 비치환 또는 C1-6 알킬, C1-6 알콕시, 할로겐, 시아노, C1-6 할로알킬 및 C1-6 할로알콕시로 구성된 군으로부터 선택되는 하나 이상으로 치환됨.
- 제1항에 있어서,L은 -NHCO-, -CONH-, -NHSO2-, -SO2NH-, -O-, -O-CH2-, -O-(CH2)2-, 또는 -O-CH(CH3)-인 것인, 화합물 또는 이의 약학적으로 허용 가능한 염.
- 제1항에 있어서,R1은 수소, 메틸, 또는 아세틸;(Het)Ar1은 페닐렌, 피리디닐렌, 피라지닐렌, 피리미디닐렌, 피라졸릴렌, 피리다지닐렌, 티오페닐렌, 벤조티아졸릴렌, 티아졸로피리디닐렌, 퀴녹살리닐렌, 티아졸릴렌, 이속사졸릴렌, 옥사졸릴렌, 퓨라닐렌, 벤조이미다졸릴렌, 벤조티오페닐렌, 또는 벤조옥사졸릴렌;(Het)Ar2는 페닐, 피리디닐, 피라지닐, 피리미디닐, 피라졸릴, 피리다지닐, 티오페닐, 벤조티아졸릴, 티아졸로피리디닐, 퀴녹살리닐, 티아졸릴, 이속사졸릴, 옥사졸릴, 퓨라닐, 벤조이미다졸릴, 벤조티오페닐, 또는 벤조옥사졸릴;상기 (Het)Ar1 및 (Het)Ar2는 각각 독립적으로 비치환 또는 메틸, 메톡시, 플루오로, 클로로, 시아노, 및 트리플루오로메틸로 구성된 군으로부터 선택되는 하나 이상으로 치환된 것인, 화합물 또는 이의 약학적으로 허용 가능한 염.
- 제1항에 있어서,R1은 수소, 메틸, 또는 아세틸;(Het)Ar1은 페닐렌, 피리디닐렌, 또는 티아졸로피리디닐렌;(Het)Ar2는 페닐, 피리디닐, 피라지닐, 피리미디닐, 피라졸릴, 피리다지닐, 티오페닐, 벤조티아졸릴, 퀴녹살리닐, 티아졸릴, 이속사졸릴, 옥사졸릴, 퓨라닐, 벤조이미다졸릴, 벤조티오페닐, 또는 벤조옥사졸릴;상기 (Het)Ar1 및 (Het)Ar2는 각각 독립적으로 비치환 또는 메틸, 메톡시, 플루오로, 클로로, 시아노, 및 트리플루오로메틸로 구성된 군으로부터 선택되는 하나 이상으로 치환된 것인, 화합물 또는 이의 약학적으로 허용 가능한 염.
- 제1항에 있어서,상기 화합물은1. (6-(5-메틸피라진-2-카르복사미도)피리딘-3-일)카르보노하이드라조노일 디시아나이드,2. (4-(5-메틸피라진-2-카르복사미도)페닐)카르보노하이드라조노일 디시아나이드,3. (2-플루오로-4-(5-메틸피라진-2-카르복사미도)페닐)카르보노하이드라조노일 디시아나이드,4. (2-메톡시-4-(5-메틸피라진-2-카르복사미도)페닐)카르보노하이드라조노일 디시아나이드,5. (2-클로로-4-(5-메틸피라진-2-카르복사미도)페닐)카르보노하이드라조노일 디시아나이드,6. (2-메틸-4-(5-메틸피라진-2-카르복사미도)페닐)카르보노하이드라조노일 디시아나이드,7. (3-플루오로-4-(5-메틸피라진-2-카르복사미도)페닐)카르보노하이드라조노일 디시아나이드,8. (3-메틸-4-(5-메틸피라진-2-카르복사미도)페닐)카르보노하이드라조노일 디시아나이드,9. 메틸(3-메틸-4-(5-메틸피라진-2-카르복사미도)페닐)카르보노하이드라조노일 디시아나이드,10. (3-메톡시-4-(5-메틸피라진-2-카르복사미도)페닐)카르보노하이드라조노일 디시아나이드,11. (3-클로로-4-(5-메틸피라진-2-카르복사미도)페닐)카르보노하이드라조노일 디시아나이드,12. (5-메틸-6-(5-메틸피라진-2-카르복사미도)피리딘-3-일)카르보노하이드라조노일 디시아나이드,13. (4-메틸-6-(5-메틸피라진-2-카르복사미도)피리딘-3-일)카르보노하이드라조노일 디시아나이드,14. (5-(5-메틸피라진-2-카르복사미도)피리딘-2-일)카르보노하이드라조노일 디시아나이드,15. (6-벤즈아미도피리딘-3-일)카르보노하이드라조노일 디시아나이드,16. (6-(4-플루오로벤즈아미도)피리딘-3-일)카르보노하이드라조노일 디시아나이드,17. (6-(2-플루오로벤즈아미도)피리딘-3-일)카르보노하이드라조노일 디시아나이드,18. (6-(3-플루오로벤즈아미도)피리딘-3-일)카르보노하이드라조노일 디시아나이드,19. (6-(3-플루오로-5-메틸벤즈아미도)피리딘-3-일)카르보노하이드라조노일 디시아나이드,20. (6-(2-플루오로-3-메틸벤즈아미도)피리딘-3-일)카르보노하이드라조노일 디시아나이드,21. (6-(4-플루오로-3-메틸벤즈아미도)피리딘-3-일)카르보노하이드라조노일 디시아나이드,22. (6-(3-플루오로-4-메틸벤즈아미도)피리딘-3-일)카르보노하이드라조노일 디시아나이드,23. (6-(4-메틸벤즈아미도)피리딘-3-일)카르보노하이드라조노일 디시아나이드,24. (6-(3-메틸벤즈아미도)피리딘-3-일)카르보노하이드라조노일 디시아나이드,25. (6-(2-메틸벤즈아미도)피리딘-3-일)카르보노하이드라조노일 디시아나이드,26. (6-(3-(트리플루오로메틸)벤즈아미도)피리딘-3-일)카르보노하이드라조노일 디시아나이드,27. (6-(4-(트리플루오로메틸)벤즈아미도)피리딘-3-일)카르보노하이드라조노일 디시아나이드,28. (6-(2-(트리플루오로메틸)벤즈아미도)피리딘-3-일)카르보노하이드라조노일 디시아나이드,29. (6-(피리미딘-2-카르복사미도)피리딘-3-일)카르보노하이드라조노일 디시아나이드,30. (6-(티오펜-2-카르복사미도)피리딘-3-일)카르보노하이드라조노일 디시아나이드,31. (6-(벤조[d]티아졸-2-카르복사미도)피리딘-3-일)카르보노하이드라조노일 디시아나이드,32. (6-(퀴녹살린-2-카르복사미도)피리딘-3-일)카르보노하이드라조노일 디시아나이드,33. (2-(5-메틸피라진-2-카르복사미도)티아졸로[4,5-b]피리딘-6-일)카르보노하이드라조노일 디시아나이드,34. (6-(p-톨릴카바모일)피리딘-3-일)카르보노하이드라조노일 디시아나이드,35. (6-(4-메톡시페닐카바모일)피리딘-3-일)카르보노하이드라조노일 디시아나이드,36. (6-(5-메틸피라진-2-일카바모일)피리딘-3-일)카르보노하이드라조노일 디시아나이드,37. (6-(4-클로로페닐카바모일)피리딘-3-일)카르보노하이드라조노일 디시아나이드,38. (6-(6-메틸피리딘-3-일카바모일)피리딘-3-일)카르보노하이드라조노일 디시아나이드,39. (6-(5-메틸피리딘-3-일카바모일)피리딘-3-일)카르보노하이드라조노일 디시아나이드,40. (6-(피리딘-3-일카바모일)피리딘-3-일)카르보노하이드라조노일 디시아나이드,41. (6-(6-메틸피라진-2-일카바모일)피리딘-3-일)카르보노하이드라조노일 디시아나이드,42. (6-(피리미딘-5-일카바모일)피리딘-3-일)카르보노하이드라조노일 디시아나이드,43. (6-(피리미딘-2-일카바모일)피리딘-3-일)카르보노하이드라조노일 디시아나이드,44. (4-(4-메톡시페닐카바모일)페닐)카르보노하이드라조노일 디시아나이드,45. (4-(5-메틸피라진-2-일카바모일)페닐)카르보노하이드라조노일 디시아나이드,46. (4-(6-메틸피라진-2-일카바모일)페닐)카르보노하이드라조노일 디시아나이드,47. (4-(6-메틸피리딘-3-일카바모일)페닐)카르보노하이드라조노일 디시아나이드,48. (4-(5-메틸피리딘-3-일카바모일)페닐)카르보노하이드라조노일 디시아나이드,49. (4-(피리딘-3-일카바모일)페닐)카르보노하이드라조노일 디시아나이드,50. (4-(피리미딘-5-일카바모일)페닐)카르보노하이드라조노일 디시아나이드,51. (2-메톡시-4-(5-메틸피라진-2-일카바모일)페닐)카르보노하이드라조노일 디시아나이드,52. (3-메틸-4-(5-메틸피라진-2-일카바모일)페닐)카르보노하이드라조노일 디시아나이드,53. (3-메틸-4-(6-메틸피리딘-3-일카바모일)페닐)카르보노하이드라조노일 디시아나이드,54. (3-메틸-4-(6-메틸피라진-2-일카바모일)페닐)카르보노하이드라조노일 디시아나이드,55. (2-메틸-4-(6-메틸피리딘-3-일카바모일)페닐)카르보노하이드라조노일 디시아나이드,56. (2-플루오로-4-(5-메틸피라진-2-일카바모일)페닐)카르보노하이드라조노일 디시아나이드,57. (2-메톡시-4-(6-메틸피리딘-3-일카바모일)페닐)카르보노하이드라조노일 디시아나이드,58. (6-(페닐술폰아미도)피리딘-3-일)카르보노하이드라조노일 디시아나이드,59. (6-(4-메톡시페닐술폰아미도)피리딘-3-일)카르보노하이드라조노일 디시아나이드,60. (6-(피리딘-3-술폰아미도)피리딘-3-일)카르보노하이드라조노일 디시아나이드,61. (6-(1-메틸-1H-피라졸-4-술폰아미도)피리딘-3-일)카르보노하이드라조노일 디시아나이드,62. (6-(티오펜-2-술폰아미도)피리딘-3-일)카르보노하이드라조노일 디시아나이드,63. (6-(4-메틸페닐술폰아미도)피리딘-3-일)카르보노하이드라조노일 디시아나이드,64. (6-(4-플루오로페닐술폰아미도)피리딘-3-일)카르보노하이드라조노일 디시아나이드,65. (4-(N-(6-메틸피리딘-3-일)술파모일)페닐)카르보노하이드라조노일 디시아나이드,66. (4-(N-(4-메톡시페닐)술파모일)페닐)카르보노하이드라조노일 디시아나이드,67. (4-(N-(5-메틸피라진-2-일)술파모일)페닐)카르보노하이드라조노일 디시아나이드,68. (6-페녹시피리딘-3-일)카르보노하이드라조노일 디시아나이드,69. (6-(3-플루오로페녹시)피리딘-3-일)카르보노하이드라조노일 디시아나이드,70. (5-페녹시피리딘-2-일)카르보노하이드라조노일 디시아나이드,71. (3-플루오로-4-페녹시페닐)카르보노하이드라조노일 디시아나이드,72. (3-플루오로-4-(피리딘-3-일옥시)페닐)카르보노하이드라조노일 디시아나이드,73. (4-페녹시-3-(트리플루오로메틸)페닐)카르보노하이드라조노일 디시아나이드,74. (3-메틸-4-(피리딘-3-일옥시)페닐)카르보노하이드라조노일 디시아나이드,75. 메틸(5-페녹시피리딘-2-일)카르보노하이드라조노일 디시아나이드,76. (6-(3-플루오로페녹시)피리딘-3-일)(메틸)카르보노하이드라조노일 디시아나이드,77. (3-플루오로-4-페녹시페닐)(메틸)카르보노하이드라조노일 디시아나이드,78. 메틸(4-페녹시-3-(트리플루오로메틸)페닐)카르보노하이드라조노일 디시아나이드,79. (3-메틸-4-(피리딘-4-일옥시)페닐)카르보노하이드라조노일 디시아나이드,80. (3-플루오로-4-(피리딘-4-일옥시)페닐)카르보노하이드라조노일 디시아나이드,81. (3-메틸-4-(피리미딘-5-일옥시)페닐)카르보노하이드라조노일 디시아나이드,82. (3-플루오로-4-(피리미딘-5-일옥시)페닐)카르보노하이드라조노일 디시아나이드,83. (4-(피리딘-2-일옥시)페닐)카르보노하이드라조노일 디시아나이드,84. (4-(피라진-2-일옥시)페닐)카르보노하이드라조노일 디시아나이드,85. (4-(피리딘-3-일옥시)페닐)카르보노하이드라조노일 디시아나이드,86. (4-(2-시아노페녹시)페닐)카르보노하이드라조노일 디시아나이드,87. (4-(4-시아노페녹시)페닐)카르보노하이드라조노일 디시아나이드,88. (4-(3-시아노페녹시)페닐)카르보노하이드라조노일 디시아나이드,89. (4-(6-(트리플루오로메틸)피리딘-3-일옥시)페닐)카르보노하이드라조노일 디시아나이드,90. (4-(5-(트리플루오로메틸)피리딘-2-일옥시)페닐)카르보노하이드라조노일 디시아나이드,91. (4-(피리미딘-2-일옥시)페닐)카르보노하이드라조노일 디시아나이드,92. (4-(피리다진-3-일옥시)페닐)카르보노하이드라조노일 디시아나이드,93. (4-(2-플루오로페녹시)페닐)카르보노하이드라조노일 디시아나이드,94. (4-(3-플루오로페녹시)페닐)카르보노하이드라조노일 디시아나이드,95. (6-(벤질옥시)피리딘-3-일)카르보노하이드라조노일 디시아나이드,96. (6-(4-(트리플루오로메틸)벤질옥시)피리딘-3-일)카르보노하이드라조노일 디시아나이드,97. (4-(벤질옥시)-3-(트리플루오로메틸)페닐)카르보노하이드라조노일 디시아나이드,98. (3-(트리플루오로메틸)-4-(4-(트리플루오로메틸)벤질옥시)페닐)카르보노하이드라조노일 디시아나이드,99. (6-(4-메틸벤질옥시)피리딘-3-일)카르보노하이드라조노일 디시아나이드,100. (6-페네톡시피리딘-3-일)카르보노하이드라조노일 디시아나이드,101. (4-페네톡시-3-(트리플루오로메틸)페닐)카르보노하이드라조노일 디시아나이드,102. (6-(4-메톡시페네톡시)피리딘-3-일)카르보노하이드라조노일 디시아나이드,103. (6-(4-(트리플루오로메틸)페네톡시)피리딘-3-일)카르보노하이드라조노일 디시아나이드,104. (3-메톡시-4-(5-메틸피라진-2-일카바모일)페닐)카르보노하이드라조노일 디시아나이드,105. (3-메톡시-4-(6-메틸피라진-2-일카바모일)페닐)카르보노하이드라조노일 디시아나이드,106. (3-클로로-4-(5-메틸피라진-2-일카바모일)페닐)카르보노하이드라조노일 디시아나이드,107. (3-메톡시-4-(5-메틸피리딘-3-일카바모일)페닐)카르보노하이드라조노일 디시아나이드,108. (3-메톡시-4-(p-톨릴카바모일)페닐)카르보노하이드라조노일 디시아나이드,109. (3-메톡시-4-(4-메톡시페닐카바모일)페닐)카르보노하이드라조노일 디시아나이드,110. (6-(퓨란-3-카르복사미도)피리딘-3-일)카르보노하이드라조노일 디시아나이드,111. (3-메틸-4-(티아졸-4-카르복사미도)페닐)카르보노하이드라조노일 디시아나이드,112. (6-(티아졸-4-카르복사미도)피리딘-3-일)카르보노하이드라조노일 디시아나이드,113. (6-(옥사졸-4-카르복사미도)피리딘-3-일)카르보노하이드라조노일 디시아나이드,114. (6-(옥사졸-5-카르복사미도)피리딘-3-일)카르보노하이드라조노일 디시아나이드,115. (6-(이속사졸-3-카르복사미도)피리딘-3-일)카르보노하이드라조노일 디시아나이드,116. (4-(티아졸-2-일옥시)페닐)카르보노하이드라조노일 디시아나이드,117. (4-(벤질옥시)페닐)카르보노하이드라조노일 디시아나이드,118. (4-(4-(트리플루오로메틸)벤질옥시)페닐)카르보노하이드라조노일 디시아나이드,119. (4-(4-메틸벤질옥시)페닐)카르보노하이드라조노일 디시아나이드,120. (4-(4-메톡시페네톡시)페닐)카르보노하이드라조노일 디시아나이드,121. (4-(4-(트리플루오로메틸)페네톡시)페닐)카르보노하이드라조노일 디시아나이드,122. (4-페네톡시페닐)카르보노하이드라조노일 디시아나이드,123. (4-(4-클로로페네톡시)페닐)카르보노하이드라조노일 디시아나이드,124. (4-(피리딘-3-일메톡시)페닐)카르보노하이드라조노일 디시아나이드,125. (4-(피라진-2-일메톡시)페닐)카르보노하이드라조노일 디시아나이드,126. (4-((1H-벤조[d]이미다졸-2-일)메톡시)페닐)카르보노하이드라조노일 디시아나이드,127. (4-(피리다진-3-일메톡시)페닐)카르보노하이드라조노일 디시아나이드,128. (4-(벤조[d]옥사졸-2-일메톡시)페닐)카르보노하이드라조노일 디시아나이드,129. (4-(벤조[d]티아졸-2-일메톡시)페닐)카르보노하이드라조노일 디시아나이드,130. (4-(벤조[b]티오펜-2-일메톡시)페닐)카르보노하이드라조노일 디시아나이드,131. (6-(4-클로로페네톡시)피리딘-3-일)카르보노하이드라조노일 디시아나이드,132. (4-(4-메틸벤질옥시)-3-(트리플루오로메틸)페닐)카르보노하이드라조노일 디시아나이드,133. (4-(4-클로로페네톡시)-3-(트리플루오로메틸)페닐)카르보노하이드라조노일 디시아나이드,134. (4-(4-메톡시페네톡시)-3-(트리플루오로메틸)페닐)카르보노하이드라조노일 디시아나이드,135. (3-(트리플루오로메틸)-4-(4-(트리플루오로메틸)페네톡시)페닐)카르보노하이드라조노일 디시아나이드,136. (4-(피리미딘-2-일메톡시)페닐)카르보노하이드라조노일 디시아나이드,137. (4-((1H-피라졸-4-일)메톡시)페닐)카르보노하이드라조노일 디시아나이드,138. (4-((5-메틸피라진-2-일)메톡시)페닐)카르보노하이드라조노일 디시아나이드,139. (4-(1-(4-(트리플루오로메틸)페닐)에톡시)페닐)카르보노하이드라조노일 디시아나이드,140. (4-(1-(피리딘-3-일)에톡시)페닐)카르보노하이드라조노일 디시아나이드,141. (4-(벤질옥시)-3-메틸페닐)카르보노하이드라조노일 디시아나이드,142. (3-메틸-4-(4-메틸벤질옥시)페닐)카르보노하이드라조노일 디시아나이드,143. (3-메틸-4-(피리미딘-2-일메톡시)페닐)카르보노하이드라조노일 디시아나이드,144. (3-메틸-4-(피라진-2-일메톡시)페닐)카르보노하이드라조노일 디시아나이드,145. (3-메틸-4-(피리딘-3-일메톡시)페닐)카르보노하이드라조노일 디시아나이드,146. (4-((1H-벤조[d]이미다졸-2-일)메톡시)-3-메틸페닐)카르보노하이드라조노일 디시아나이드,147. (3-메틸-4-((5-메틸피라진-2-일)메톡시)페닐)카르보노하이드라조노일 디시아나이드,148. (3-메틸-4-(4-(트리플루오로메틸)벤질옥시)페닐)카르보노하이드라조노일 디시아나이드,149. (3-메틸-4-(피리다진-3-일메톡시)페닐)카르보노하이드라조노일 디시아나이드,150. (4-(벤조[b]티오펜-2-일메톡시)-3-메틸페닐)카르보노하이드라조노일 디시아나이드,151. (4-((1H-피라졸-3-일)메톡시)-3-메틸페닐)카르보노하이드라조노일 디시아나이드,152. (3-메틸-4-(티아졸-4-일메톡시)페닐)카르보노하이드라조노일 디시아나이드,153. (4-(벤질옥시)-3-메톡시페닐)카르보노하이드라조노일 디시아나이드,154. (3-메톡시-4-(4-메틸벤질옥시)페닐)카르보노하이드라조노일 디시아나이드,155. (3-메톡시-4-(4-(트리플루오로메틸)벤질옥시)페닐)카르보노하이드라조노일 디시아나이드,156. (4-(벤조[d]옥사졸-2-일메톡시)-3-메틸페닐)카르보노하이드라조노일 디시아나이드,157. (4-(벤조[d]티아졸-2-일메톡시)-3-메틸페닐)카르보노하이드라조노일 디시아나이드,158. (4-(벤조[b]티오펜-2-일메톡시)-3-메톡시페닐)카르보노하이드라조노일 디시아나이드,159. (3-메톡시-4-(피라진-2-일메톡시)페닐)카르보노하이드라조노일 디시아나이드,160. (3-메톡시-4-(피리딘-3-일메톡시)페닐)카르보노하이드라조노일 디시아나이드,161. (3-메톡시-4-(피리미딘-2-일메톡시)페닐)카르보노하이드라조노일 디시아나이드,162. (3-메톡시-4-((5-메틸피라진-2-일)메톡시)페닐)카르보노하이드라조노일 디시아나이드,163. (4-((1H-벤조[d]이미다졸-2-일)메톡시)-3-메톡시페닐)카르보노하이드라조노일 디시아나이드,164. (3-메톡시-4-(피리다진-3-일메톡시)페닐)카르보노하이드라조노일 디시아나이드,165. (4-(벤조[d]티아졸-2-일메톡시)-3-메톡시페닐)카르보노하이드라조노일 디시아나이드,166. (4-(벤조[d]옥사졸-2-일메톡시)-3-메톡시페닐)카르보노하이드라조노일 디시아나이드,167. (3-메톡시-4-(티아졸-4-일메톡시)페닐)카르보노하이드라조노일 디시아나이드,168. (4-((1H-피라졸-3-일)메톡시)-3-메톡시페닐)카르보노하이드라조노일 디시아나이드,169. (3-메톡시-4-(피리딘-2-일메톡시)페닐)카르보노하이드라조노일 디시아나이드,170. (3-메톡시-4-((6-메틸피리딘-3-일)메톡시)페닐)카르보노하이드라조노일 디시아나이드,171. (3-메톡시-4-((2-메틸티아졸-4-일)메톡시)페닐)카르보노하이드라조노일 디시아나이드,172. (3-메톡시-4-(티오펜-2-일메톡시)페닐)카르보노하이드라조노일 디시아나이드,173. (3-메톡시-4-(티오펜-3-일메톡시)페닐)카르보노하이드라조노일 디시아나이드,174. (3-메톡시-4-((1-메틸-1H-피라졸-4-일)메톡시)페닐)카르보노하이드라조노일 디시아나이드, 또는175. 아세틸(3-메틸-4-(4-메틸벤질옥시)페닐)카르보노하이드라조노일 디시아나이드인 것인, 화합물 또는 이의 약학적으로 허용 가능한 염.
- 제6항에 있어서,상기 제1단계는C1-4 저급알코올 용매에 화학식 2의 화합물과 아질산나트륨을 용해시키고, -5 내지 5℃에서 산 수용액을 첨가하여 디아조늄 염을 형성하는 제1-1단계,상기 제1-1단계로부터 수득한 다이아조늄 염을 포함하는 반응 용액에 말로노니트릴을 첨가하여 15 내지 40℃에서 반응시키는 제1-2단계, 및상기 제1-2단계의 반응 용액에 염기 수용액을 첨가하여 중화하는 제1-3단계를 포함하는 일련의 과정에 의해 수행되는 것인, 제조방법.
- 제8항에 있어서,L이 -NHCO- 또는 -CONH-인 경우, 화학식 3의 화합물은 각각i) 니트로기 및 상기 L과 연결되는 자리에 카르복실기를 포함하는 (Het)Ar1 유도체와 상기 L과 연결되는 자리에 아민기를 포함하는 (Het)Ar2 유도체를; 또는ii) 니트로기 및 상기 L과 연결되는 자리에 아민기를 포함하는 (Het)Ar1 유도체와 상기 L과 연결되는 자리에 카르복실기를 포함하는 (Het)Ar2 유도체를반응시켜 준비되는 것인, 제조방법.
- 제8항에 있어서,L이 -NHSO2- 또는 -SO2NH-인 경우, 화학식 3의 화합물은 각각i) 니트로기 및 상기 L과 연결되는 자리에 아민기를 포함하는 (Het)Ar1 유도체와 상기 L과 연결되는 자리에 할로설포닐기를 포함하는 (Het)Ar2 유도체를; 또는ii) 니트로기 및 상기 L과 연결되는 자리에 클로로설포닐기를 포함하는 (Het)Ar1 유도체와 상기 L과 연결되는 자리에 아민기를 포함하는 (Het)Ar2 유도체를반응시켜 준비되는 것인, 제조방법.
- 제8항에 있어서,L이 -(직쇄 또는 분지쇄 C0-3 알킬렌)'-O-(직쇄 또는 분지쇄 C0-3 알킬렌)"-인 경우, 화학식 3의 화합물은i) 니트로기 및 상기 L과 연결되는 자리에 -(직쇄 또는 분지쇄 C0-3 알킬렌)'-OH를 포함하는 (Het)Ar1 유도체와 상기 L과 연결되는 자리에 -(직쇄 또는 분지쇄 C0-3 알킬렌)"-X(X는 할로겐)를 포함하는 (Het)Ar2 유도체를; 또는ii) 니트로기 및 상기 L과 연결되는 자리에 -(직쇄 또는 분지쇄 C0-3 알킬렌)'-X를 포함하는 (Het)Ar1 유도체와 상기 L과 연결되는 자리에 -(직쇄 또는 분지쇄 C0-3 알킬렌)"-OH를 포함하는 (Het)Ar2 유도체를반응시켜 준비되는 것인, 제조방법.
- 제1항의 화합물을 유효성분으로 포함하는 타우 단백질(tau protein) 응집 저해용 조성물.
- 제1항의 화합물을 유효성분으로 포함하는 타우 단백질 과인산화 저해용 조성물.
- 제1항의 화합물을 유효성분으로 포함하는 타우 단백질의 응집 또는 과인산화에 의해 유발되는 질환의 예방 또는 치료용 약학적 조성물.
- 제14항에 있어서,상기 타우 단백질의 응집 또는 과인산화에 의해 유발되는 질환은 알츠하이머 질환, 파킨슨 질환, 혈관성 치매, 급성 뇌졸증, 외상, 뇌혈관 질환, 뇌 코드 외상, 척수 외상, 말초 신경병증, 망막병증, 녹내장 및 타우병증(tauopathies)으로 구성된 군으로부터 선택된 것인 약학적 조성물.
- 제15항에 있어서,상기 타우병증은 만성 외상성 뇌병증(chronic traumatic encephalopathy; CTE), 원발성 연령관련 타우병증(primary age-related tauopathy), 진행성 핵상 마비(progressive supranuclear palsy), 피질기저퇴행증(corticobasal degeneration), 피크 질환(Pick's disease), 아지오필릭 그레인 질환(argyrophilic grain disease; AGD), 전측두엽 치매(frontotemporal dementia; FTD), 17번 염색체 관련 파킨슨증(Parkinsonism linked to chromosome 17), 리티코-보디그 질환(Lytico-Bodig disease, Parkinson-dementia complex of Guam), 신경절교세포증(ganglioglioma), 신경세포종(gangliocytoma), 수막혈관주위세포종(meningioangiomatosis), 뇌염후 파킨슨증(postencephalitic parkinsonism), 아급성 경화성 범뇌염(subacute sclerosing panencephalitis), 연독성뇌증(lead encephalopathy), 결절성경화증(tuberous sclerosis), 판토테네이트 키나아제 결합 신경 퇴화(Pantothenate kinase-associated neurodegeneration), 지방갈색소증(lipofuscinosis), 외상후 스트레스 장애(posttraumatic stress disorder), 및 외상성 뇌손상(traumatic brain injury)으로 구성된 군으로부터 선택된 것인 약학적 조성물.
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